title: Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A).
abstract: Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Molecular Structure, §Department of Pharmacokinetics and Drug Metabolism, ∥Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Shannon
authors.initials: S
authors.lastname: Rumfelt
authors.forename: Aaron
authors.initials: A
authors.lastname: Siegmund
authors.forename: Kristin
authors.initials: K
authors.lastname: Andrews
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhao
authors.forename: Carl
authors.initials: C
authors.lastname: Davis
authors.forename: Hang
authors.initials: H
authors.lastname: Chen
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Christopher
authors.initials: C
authors.lastname: Biorn
authors.forename: Jianxia
authors.initials: J
authors.lastname: Shi
authors.forename: Amy
authors.initials: A
authors.lastname: Porter
authors.forename: James
authors.initials: J
authors.lastname: Treanor
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D001562:Benzimidazoles; D007659:Ketones; D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases